MHC class I genes are transcriptionally regulated through the basal promoter and regulatory elements in the 5' flanking sequence, to achieve varying tissue-specific levels of expression which are further dynamically modulated in response to extracellular signals. The class I basal promoter consists of three elements: a TATAA box, an initiator (Inr), and a novel S-box element. The transcription factor USF activates class I transcription through the initiator. The S-box, which is required for both TATAA and Inr mediated initiation, interacts with both Sp1 and the single-strand DNA binding protein, YB1, which respectively activate and repress the promoter. The relative usage of TATAA and Inr elements varies among different cell types. The functional basis of this promoter selectivity is under investigation. Basal transcription of class I genes varies among tissues as a result of negative regulation mediated by a series of silencers located between approximately -400 and -1100 bp. The major tissue specific regulatory domain spans the region -700bp to -800bp, and consists of overlapping enhancer and silencer elements. Enhancer activity is present in all cell types, whereas silencer activity is inversely proportional to the level of class I expresssion. The enhancer factor consists of Oct 1 in association with a novel, glycosylated, redox-sensitive factor; the silencer factor is also a complex, containing ATF2. Additional silencer elements contribute to the negative regulation. In human neuronal cells the failure to express class I is due to the activities of four distinct silencer elements. In addition to the -700 to -800 silencer element, additional elements occur between -400 and -500bp. Removal of these upstream silencers not only results in active expression of the class I promoter in neuronal cells, but also reveals the presence of an active enhancer. This repression of a functional promoter provides a mechanism for rapid and specific triggering of class I in neuronal cells in response to infection.